ClinVar Miner

Submissions for variant NM_000463.3(UGT1A1):c.1130G>T (p.Gly377Val)

gnomAD frequency: 0.00001  dbSNP: rs1283652721
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001817729 SCV002069073 pathogenic not provided 2018-01-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001817729 SCV002220383 pathogenic not provided 2021-08-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 377 of the UGT1A1 protein (p.Gly377Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Crigler-Najjar syndrome type 2 (PMID: 11013440, 15712364, 18058623). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003317533 SCV004020628 uncertain significance not specified 2023-06-05 criteria provided, single submitter clinical testing Variant summary: UGT1A1 c.1130G>T (p.Gly377Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249054 control chromosomes. c.1130G>T has been reported in the literature as a non-informative genotype (second allele not specified) (Kadakol_2000), in compound heterozygosity with other putatively pathogenic and/or VUS UGT1A1 variants (Servedio_2005, Li_2015), reportedly in cis with another UGT1A1 variant (Perretti_2007) in individuals affected with Crigler-Najjar syndrome. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11013440, 25993113, 18058623, 15712364). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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